International Hit Parade

In Buenos Aires the midwinter days are short and the weather cool like summer in San Francisco. The International AIDS Society (IAS) chose Argentina to initiate its new pathogenesis and treatment biennial, which will fall during the off-years between the much larger International AIDS Conferences. Although new data was sparse, here is a look at three of the meeting's "greatest hits."

Hit Even Harder

David Ho treated us to a review of career highlights from his work on viral dynamics during the five years since his earthshaking Vancouver presentation. In doing so he proved that -- as Prince observed in a song from Graffiti Bridge -- there is indeed joy in repetition. At the end of the talk he showed us that a five-drug regimen consisting of lopinavir/ritonavir with 3TC, efavirenz and tenofovir can cut the first phase of viral decay from 14 days (shown with AZT/3TC/ritonavir back at Vancouver) to just seven days. It's too soon to say whether this regimen will also accelerate subsequent, slower phases of decay, which David attributes to virus produced from macrophages. It's remarkable just how little research has been done on this second compartment. Macrophages are terminally differentiated and found in tissue, not blood, and thus are much harder to sample than the latently infected CD4 T cell about which so much has been written. If the five-drug regimen also accelerates the second and third phases of viral decay, then perhaps we can look forward to eradicating HIV from the body by taking HAART without a single slip-up in only thirty years instead of sixty. What fun!

Hit Even Later

Julio Montaner, updating us on the British Columbia HIV cohort, showed that baseline CD4 count when starting treatment is highly predictive of hospitalization, AIDS, and survival -- with baseline CD4 count below 200 being bad and one below 50 very bad indeed. However, if baseline CD4 counts are adjusted with data for adherence, then, remarkably, people who started treatment with CD4 counts below 50 -- if they'd been highly adherent to their regimens -- had survival results equivalent to those of people who entered the cohort at higher CD4 counts.

This reminds us that individuals with quite low CD4 counts can be rescued. John Mellors just hates this data, though it doesn't in the least undermine the prime lesson from his important analysis of the prognostic value of viral load levels using banked blood samples from 1985. The Mellors data showed that viral load shortly after infection strongly predicted the rate of CD4 cell loss and hence the rate of disease progression. Montaner's data show that, in the short term at least, CD4 count, especially at low levels, is more predictive of clinical outcome. These data don't prove that it's better to start later -- but they don't support the notion of hitting at levels much above 200 CD4 cells either. That shredding sound represents five years of misguided guidelines being ripped to pieces.

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Hit Intermittently

Tony Fauci kicked off the conference proper with an update on structured intermittent therapy (SIT) using a long cycle (60 days on treatment, 30 days off) and a short cycle (7 days on, 7 off). The long cycle was less than optimal since viral loads tended to rebound during the off phase and did not always decline fully after restarting treatment -- which in some cases apparently led to drug resistance.

The short cycle SIT, however, at 32 cycles (64 weeks) into the experiment, continues to look pretty good. Ten people who had achieved good viral control on HAART were enrolled. For the eight remaining in the study after 60-64 weeks, there was no change in absolute CD4 count, CD4 percentage, CD8 count, activation markers, plasma HIV RNA, cellular HIV RNA, proviral HIV RNA, or latently infected CD4 cell count. The data were "obvious and monotonous" in these respects, commented Fauci. Lymph node biopsies were similarly unremarkable and unchanged. No drug resistance mutations had appeared. So far, so good. The really interesting part was that triglycerides, total cholesterol and LDL cholesterol all dropped significantly from week 0 to week 24 and continued dropping out to week 52. So, at least in this handful of patients, the short-cycle SIT appears to preserve antiviral efficacy while reducing common and potentially serious HAART-associated toxicity. Larger randomized, controlled studies are urgently needed.

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